NASA Technical Reports Server (NTRS) 20170009794: Advantage of Animal Models with Metabolic Flexibility for Space Research Beyond Low Earth Orbit Advantage of Animal Models with Metabolic Flexibility for Space Research Beyond Low Earth Orbit

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by  NASA Technical Reports Server (NTRS)

Advantage of animal models with metabolic flexibility for space research
beyond Low Earth Orbit

Yuri V. Griko1*, Jon C. Rask2, Raycho Raychev3

1,2 NASA Ames Research Center, Moffett Field, CA 94035
3 Space Challenges Program, EnduroSat Inc. Sofia, Bulgaria

*Corresponding author: Space Biosciences Division, NASA Ames Research Center, MS261-3,
Moffett Field, CA 94035, USA. Tel: [phone]; fax: [phone]
Email: [email protected] (Y.V. Griko).

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Abstract: As the world’s space agencies and commercial entities continue to expand beyond
Low Earth Orbit (LEO), novel approaches to carry out biomedical experiments with animals are
required to address the challenge of adaptation to space flight and new planetary environments.
The extended time and distance of space travel along with reduced involvement of Earth-based
mission support increases the cumulative impact of the risks encountered in space. To respond to
these challenges, it becomes increasingly important to develop the capability to manage an
organism’s self-regulatory control system, which would enable survival in extraterrestrial
environments. To significantly reduce the risk to animals on future long duration space
missions, we propose the use of metabolically flexible animal models as “pathfinders,” which are
capable of tolerating the environmental extremes exhibited in spaceflight, including altered
gravity, exposure to space radiation, chemically reactive planetary environments and temperature
extremes.
In this report we survey several of the pivotal metabolic flexibility studies and discuss the
importance of utilizing animal models with metabolic flexibility with particular attention given
to the ability to suppress the organism's metabolism in spaceflight experiments beyond LEO. The
presented analysis demonstrates the adjuvant benefits of these factors to minimize damage
caused by exposure to spaceflight and extreme planetary environments. Examples of
microorganisms and animal models with dormancy capabilities suitable for space research are
considered in the context of their survivability under hostile or deadly environments outside of
Earth. Potential steps toward implementation of metabolic control technology in spaceflight
architecture and its benefits for animal experiments and manned space exploration missions are
discussed.

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Key words: spaceflight, animal research, metabolic flexibility

Introduction: While the increased human presence in orbit over the last four decades has
shown that humans can adapt to short duration spaceflight, we still have an incomplete
understanding of the adaptation to long-duration spaceflight, and little is known about health
related consequences of long-term exposure to the spaceflight environment. Future missions to
the Moon, Mars, and other deep space objects such as asteroids or moons of other planets
provide extraordinary scientific opportunities for space biologists to explore life’s ability to adapt
to the spaceflight environment during long duration missions. By studying experimental animals
aboard deep space missions, scientists can better understand the adaptive response of life to long
duration spaceflight. Results of these missions can help to define the requirements for optimal
human health in deep space as well.

Since the of era of orbital flights, animals have always preceded humans in space missions to act
as “pathfinders,” to help scientists produce new medical knowledge and test engineering design
concepts that are required to support human space exploration. Animal models are also
recognized as cost-effective solutions to probe fundamental biology questions related to human
health. Before Apollo missions to the moon, animals were used only once in space missions
beyond Low Earth Orbit (LEO). In 1968, a pair of Russian tortoises with a number of other
biological specimens, launched on a trans-lunar mission aboard the Zond 5 spacecraft, and were
the first animals from Earth which passed within 1950 km of the lunar surface and returned
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safely to Earth.1 This spacecraft was planned as a precursor to a manned lunar spacecraft. The
next time animals were sent beyond LEO was aboard the Apollo 17 mission, launched on
December 17, 1972 with the main objective to gain a better understanding of cosmic particle
radiation on animal tissues. In this mission most of the pocket mice chosen for the flight
experiments successfully survived 13-day journey after orbiting the moon2.
As long-term exploration missions by Space Agencies and commercial entities continues to
evolve and expand, we must design novel approaches to carrying out biomedical experiments
with animals based on the necessity of their long presence in space. The payoff will be
significant improvement in selecting and designing methods for optimizing adaptation to long
duration space flight.
A historical review of all animal experiments in spaceflight research since their first use in the
1950s shows that mortality of animals due to unpredictable failures in the life support systems
remains the main issue of concern being higher than the expected 5% level. Although mortality
risk among animals in space is significantly minimized in the currently available animal habitat
hardware systems developed by the National Aeronautics and Space Administration (NASA) and
the European Space Agency (ESA) to support animal research on International Space Station
(ISS), mortality rates still remain high, especially in case of non-manned autonomous
missions.3,4. Since in extended duration space flights experiments beyond LEO will likely
contribute more complications to animal welfare, it becomes important to design novel
approaches to ensure animal safety and mission outcome. One approach may be to take
advantage of altering an organism’s self-regulatory control system, which would allow the
animal survive in extraterrestrial environments.
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In this report we will briefly survey some of the pivotal studies and discuss the importance of
utilizing animal models with metabolic flexibility and particularly the ability to suppress their
metabolism in space flight experiments beyond LEO. The presented analysis demonstrates the
adjuvant benefits of this selection factor to minimize damage caused by exposure to spaceflight
and extreme planetary environments including altered gravity, elevated radiation, chemically
reactive planetary dusts, and temperature extremes.

The information, concepts, and hypotheses summarized here warrant additional studies of the
new metabolic control strategy with potential to be incorporated in space flight architecture
beyond LEO. It is also important to note this strategy is not limited to the category of animals
with naturally occurring metabolic flexibility such as hibernating animals. With the current state
of biotechnology, many other species, which are not normally capable of inducing metabolic
depression, could be intentionally pre-conditioned to this state using the metabolic control
technology. The possibility of manipulating metabolic mechanisms in animals and testing it in
long-duration missions beyond LEO may lead to development of biomedical technologies
capable of sustaining and protecting astronauts from the extreme dangers of the spaceflight
environment.

Metabolic Control as a strategy for transportation of experimental animals beyond LEO:
With growing interest in spaceflight beyond LEO, it becomes important to ensure the health and
physiological performance of animal models under spaceflight environment conditions. Upmass
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and power constraints are of paramount importance in considering the logistics of transporting
experimental animals into space. In lunar or planetary animal exploration, current animal life
support technologies have large space and mass requirements, dramatically increasing cost. In the
context of the emerging space and planetary architecture, these constraints are expected to
continue, and will greatly limit opportunities for NASA to develop a portfolio of deep space
biological research that can answer key questions of interest to both the Exploration Systems
Mission Directorate and the Science Mission Directorate. One approach to eliminate expensive
life support technologies for nominal animal metabolism during long duration spaceflight would
be to apply principals of metabolic control upon model organisms. By altering the metabolism of
animals to a minimal level during a spaceflight mission, life support requirements are reduced until
normal metabolism rates are desired. The phenomenon of the metabolic flexibility, or the ability
to reversibly alter metabolism in response to availability and need for energy, is well known for
many simple and unicellular organisms. 5,6,7,8
Metabolic suppression is defined as a drop in standard metabolic rates to less than the normal value
with energy-saving benefits toward survival in response to life-threatening environmental
stressors. The molecular mechanisms that regulate reversible transitions to and from
hypometabolic states are conserved among biologically diverse organisms and include the
coordinated reduction of specific cell processes at the genetic, molecular, cellular, organ, and
organismal levels. 9,10,11
Metabolic flexibility in its different forms, extent, and duration, is also observed in complex
organisms and could be utilized in spaceflight. Hibernation, estivation, torpor, diapause and its
extreme form cryptobiosis, when organism shows no visible signs of life, are good examples of
behaviors that may be useful for long duration spaceflight. Changes in metabolic rate of some
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organisms has been observed to be reduced by 80%, and nearly 100% in cryptobiotic
animals.12,13 The metabolic suppression is also evident in human-size animals such as the black
bear, giant panda, and even to some degree in human.14,15,16
Although metabolic suppression is a natural survival response to changes in environmental
conditions, it can also be induced in some organisms by altering factors such as temperature or
through exposure to selective chemical agents.17,18,6,7,19,20 With recent advances, it is now
possible to deliberately initiate and end dormant states in a variety of animal species that do not
naturally hibernate, demonstrating the achievement of metabolic control in a variety of “non-
hibernating” species.21,18,22,6,23,7,24

Carefully controlled studies that precondition organisms to survive hostile environmental
conditions create an opportunity for scientists to investigate metabolic control of organisms for
specific purposes related to long duration spaceflight. In the metabolically suppressed state,
animals have practically no response to any environmental factors including pathologies and
chemical toxicity, which creates an ability to potentially minimize, or even exclude their impacts.
This may be particularly useful in long duration spaceflight, and in extraterrestrial planetary
environments of altered gravity, radiation, and dusts. By using animal models that can be
metabolically controlled, scientists will be able to compare the practical advantages of
hibernating organisms to currently used animal models.
In planning for long-duration space missions, the availability of oxygen, water, and food is
critical for survival. Intentionally induced metabolic down-regulation may be a useful
operational response when the available oxygen and or food supply are limited. One of the most
profound hallmarks of metabolic suppression is a quantifiable reduction in food intake during the
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stasis. Many non-hibernating animals, which have been used in spaceflight experiments
including rodents, do not possess extensive metabolic energy reserves and therefore rely on small
fuel stores when food is limited or absent. These animals are in serious danger of death if a
source of food is not found quickly. Therefore, intentionally induced metabolic suppression will
prolong their survival over extended periods of time in absence of food.

Since humans first starting using animals in space experiments in the 1950s, animal mortality has
been a problem in some missions. However, much can be learned from those that survived in ill-
fated missions. For example, in the Bion M1 mission, the animal mortality rate was observed to
be about 75 %. It was found that all gerbils, most of the 45 mice, and all of the fish did not
survive the mission due to equipment failure. In contrast, all geckos and snails onboard Bion-M1
did survive the flight, which demonstrates the tremendous tolerance they have to hostile
environmental conditions4. Despite the high mortality rate, the Bion-M1 mission has provided
important information on the limits of survivability of organisms when exposed to unpredictable
failures in life support systems. The mission also demonstrated the importance of careful
selection of appropriate animal models to reduce risk of animal mortality.
By incorporating animal models that are capable of metabolic control into long duration space
biology experiments, the likelihood of mission success will be greatly enhanced.

Additionally, the mass and power requirement of life support systems can be reduced, making
transportation of experimental animals to other planets and deep space destination more feasible.
In space biology, differentiating between the biological effects of launch or reentry versus
fundamental responses to microgravity has always been a problem. However, this challenge
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could be overcome if animals were metabolically pre-conditioned for both launch and the return
phases of a mission. By inducing a metabolically controlled state, biological responsiveness to
the environmental factors and stress related to launch and reentry could conceivably be
eliminated. In a hypothetical experimental design, animals could be activated to a “normal”
physiological state during the desired space flight phase allowing researchers to focus completely
on spaceflight effects not related to launch or re-entry.

Furthermore, payloads that contain highly-flexible organisms with regard to operations,
experiment, and spacecraft loading requirements have significant advantages over payloads with
organisms that have limited tolerance and extensive requirements. Placing animals into a
reversible hypometabolic stasis prior to launch will also help to solve many pre-flight experiment
operational problems related to unpredictable launch delays.

Knowledge gained from the use of animals in suspended animation will provide opportunities to
gain insight into the development of mitigation strategies designed to reduce risks associated with
long duration human spaceflight. The development of solutions to other biomedical problems
where metabolic control is needed may also emerge from this work.

The study of metabolic control in spaceflight will help to address questions formulated in the
NASA Fundamental Space Biology (SB) Science Plan and the National Research Council’s 2011
Decadal Survey Report question, “How are the basic metabolic rate and metabolism of living
systems, including lifespan, affected by spaceflight?”

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Examples of microorganisms and animal models with dormancy capability suitable for space
research are summarized below. Each of these organisms possess unique metabolic mechanisms
and molecular machinery that enable them to survive in what would normally be considered
hostile or deadly environments in very unusual ways. These creatures demonstrate features
useful for spaceflight metabolic control studies and could provide synthetic biologists
information on how to engineer organisms designed to be metabolically controlled during long
duration spaceflight.

Microorganisms and small animals as models for planetary colonization: Microbes are the
most diverse and abundant type of organism on Earth. They possess billions of years of
evolutionary adaptions that have enabled them to survive in the extraordinary wide range of
physiochemical environmental conditions that exist above, on, and within the Earth. Microbes
also have the ability to suppress metabolism and remain dormant for long periods of time, and is
routinely used by a variety of organisms to overcome unfavorable environmental conditions.
Approximately 99% of all microbes on Earth are in a dormant state 25,26,27, and only a tiny
fraction is metabolically active at any given time. That dormancy and the presence of such large
reservoirs of microbial biodiversity have important implications for the stability and functioning
of ecosystem services over both short term and geologic time. Consequently, microorganisms
that are capable switching to and from the dormant state may outcompete microorganisms with
better growth performance in unfavorable environments28. These microorganisms affect entire
ecosystems on Earth, and may be involved in panspermia. Microbe-colonized rocks could be
ejected from Earth during impact processes and fall onto other planets or Moons. Similarly,
rocks from other planets, the Moon, and asteroids have landed on the Earth due to impact
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